Additive negative inotropic effect of a combination of diazepam and fentanyl

Hearts were excised from 30 male Sprague-Dawley rats and perfused in a modified Langendorff system to examine the interactions of fentanyl and diazepam on myocardial contractility as measured by left ventricular dP/dtmax. Various concentrations of fentanyl and diazepam were added to the nonrecirculating 37 degrees C perfusate to determine ED25 and ED50 for depression of dP/dtmax. Combinations of fentanyl and diazepam at a fixed negative inotropic potency ratio of 1:1 were used to determine the ED25 and ED50 of this combination. Isobolographic analyses performed at ED25 and ED50 revealed that the negative inotropic interaction of fentanyl and diazepam is purely additive. It is unlikely that a supraadditive negative inotropic effect can explain the supraadditive hemodynamic depression reported in humans when diazepam and fentanyl are combined; perhaps systemic vascular effects of this drug combination account for the clinical drug interactions.